Alzheimer's disease is a devastating neurodegenerative disorder that affects an estimated 20 million people worldwide. The disease causes progressive memory loss, cognitive decline, and ultimately death. In recent years multiple genetic mutations have been identified that can give rise to the disease, but to date the pathogenic mechanisms remain elusive. Mitochondria are an attractive candidate for analyzing Alzheimer's disease pathogenesis, as mitochondria are the primary sources of ATP and reactive oxygen species, both of which must be closely controlled to maintain neuronal health. Examination of post-mortemAlzheimer's disease tissue reveals defects in mitochondrial morphology and increased mitochondrial DMA mutation, raising the possibility that mitochondria are contributing causally to Alzheimer's disease. Mitochondria are dynamic organelles that undergo continual fission and fusion events, which are essential for mitochondrial function and intracellular distribution. Disruption of mitochondrial fusion has been implicated in multiple neurodegenerative diseases, including Charcot-Marie-Tooth disease. Actin stabilization, which is increased by tau expression, has also been demonstrated to both alter mitochondrial function and promote mitochondrial fission. It remains to be determined whether mitochondrial fission and fusion are altered in Alzheimer's disease. An excellent model system to address this question is the fruit fly Drosophila melanogaster. Alzheimer's disease is modeled in Drosophila by expression of the human disease- associated protein tau. Preliminary data in this model suggests that tau expression alters mitochondrial morphology, distribution, and function. There is also evidence that altering mitochondrial fissionreverses multiple tau-induced mitochondrial defects. It remains to be determined whether manipulating mitochondrial fission and fusion can suppress tau-induced toxicity in this model. To address this question, mitochondrial fission and fusion genes will be manipulated in adult flies and in primary cell culture to examine the effects on tau-mediated mitochondrial phenotypes and toxicity. Additionally, actin stabilization will be modulated to determine an effect on tau-induced mitochondrial abnormalities, including altered fission and fusion. Alzheimer's disease is a devastating neurodegenerative disorder that affects 20 million people worldwide, and the underlying causes of the disease remain unclear. Mitochondrial defects have been implicated in the pathogenesis of multiple neurodegenerative diseases. Post-mortem tissue analysis suggests mitochondria may be involved in Alzheimer's disease, making mitochondria a strong candidate for disease research. [unreadable] [unreadable] [unreadable]